Field of the Invention
The present invention relates to the field of pharmacotherapy of cognitive deficits in learning and memory. More particularly, the invention relates to methods for improving Cognitive Function. The present invention also relates to methods for preventing and/or treating Cognitive Impairment, in particular Mild Cognitive Impairment. The present invention further relates to methods for preventing and/or reducing the risk of developing Alzheimer's Disease in a cognitively normal subject.
Discussion of the Background
Cognitive brain disorders are characterized clinically by progressive loss of memory, cognition, reasoning, executive functioning, planning, judgment and emotional stability, gradually leading to profound mental deterioration. A wide range of disorders can lead to disturbances of cognition. Neuropsychological cognitive deficits are common in people with functional neuropsychiatric disorders such as schizophrenia. Brain disorders characterized by cognition deficits are also those associated with progressive neuronal degeneration, such as dementia, Alzheimer's Disease Parkinson's Disease, Huntington's Disease, and multiple sclerosis (MS).
Alzheimer's disease (AD) is the most common form of dementia. The basic pathological abnormalities in AD brains are amyloid plaques, neurofibrillary tangles and neuronal loss. Amyloid plaques are composed of β-amyloid peptides (Aβ) that are proteolytically produced from amyloid precursor protein (APP). APP is initially cleaved by β-secretase to generate a 99-residue carboxy-terminal fragment (CTFβ or C99) that is subsequently cleaved by γ-secretase to generate Aβ. Proteolysis by γ-secretase is heterogeneous and generates several Aβ species of different lengths. The most abundant species is a 40-residue peptide (Aβ40). A 42-residue variant (Aβ42) is also formed and, although is much less abundant than Aβ40, is more prone to fibril formation and is the initially and predominantly deposited Aβ species in AD brains. Gamma-secretase is a complex of four different membrane proteins: presenilin (PS), nicastrin, anterior pharynx-defective (Aph-1), and presenilin enhancer 2 (Pen-2). Presenilins are of exceptional pathophysiological importance since more than 150 autosomal dominant point mutations are known in these proteins, all of which cause aggressive and early-onset AD. Many point mutations of APP and PS result in increased production of Aβ42 and according to the so called “amyloid hypothesis,” the oligomeric forms of Aβ42 are the main cause of neuronal death in AD (see Lesné S, et al., Nature, 440: 352-357 (2006) and Shankar G M, et al., Nat. Med., 14: 837-842 (2008), both of which are incorporated herein by reference in their entireties). Thus, inhibition or modulation of γ-secretase appears to be a logical strategy to decrease Aβ42 accumulation in AD patients.
While a number of highly potent inhibitors of γ-secretase have been identified (see Olson R E, et al., Curr. Top. Med. Chem., 8: 17-33 (2008), which is incorporated herein by reference in its entirety), serious concerns about their toxicity have been raised since γ-secretase can cleave several other membrane proteins other than APP (see Lleo A, Curr. Top. Med. Chem., 8: 9-16 (2008), which is incorporated herein by reference in its entirety), the most pharmacologically relevant being the Notch receptor. Indeed, γ-secretase inhibitors block proteolysis of Notch by inhibiting cleavage at site 3 (see Lewis H D, et al., Biochemistry, 42: 7580-7586 (2003), which is incorporated herein by reference in its entirety). Physiological cleavage of Notch leads to release of the Notch intracellular domain (NICD), a protein fragment that is translocated to the nucleus where it regulates transcription of target genes involved in cell development and in differentiation of adult self-renewing cells. The inhibitory effects of γ-secretase inhibitors on Notch activation in embryonic and fetal development may not be of concern for the treatment of AD patients. However, it is known that Notch signaling plays an important role in the ongoing differentiation processes of the immune system (see Maillard I, et al., Immunity, 19: 781-791 (2003), which is incorporated herein by reference in its entirety), gastrointestinal tract (see Stanger B Z, et al., Proc. Natl. Acad. Sci. USA, 102: 12443-12448 (2005), which is incorporated herein by reference in its entirety) and epidermal differentiation process (see Panelos J, et al., Cancer Biol. Ther., 8: 1986-1993 (2009), which is incorporated herein by reference in its entirety). Indeed, treatment of mice with γ-secretase inhibitors can cause severe gastrointestinal toxicity and compromise the proper maturation of B- and T-lymphocytes (see Searfoss G H, et al., J. Biol. Chem., 278: 46107-46116 (2003) and Wong G T, et al., J. Biol. Chem., 279: 12876-12882 (2004), both of which are incorporated herein by reference in their entireties).
Recently, in two large 21-month Phase 3 trials conducted in more than 2,600 AD patients, an increased rate of skin cancer with semagacestat, a potent γ-secretase inhibitor, compared to placebo has been observed (see Eli Lilly and Company (2010), Lilly halts development of semagacestat for Alzheimer's disease based on preliminary results of Phase III clinical trials. Press Release Aug. 17, 2010, which is incorporated herein by reference in its entirety). In addition, an interim analysis of these two Phase 3 trials showed that cognition and the ability to complete activities of daily living of patients treated with semagacestat worsened over time to a statistically significantly higher rate than those treated with placebo (see Eli Lilly and Company (2010), Lilly halts development of semagacestat for Alzheimer's disease based on preliminary results of Phase III clinical trials. Press Release Aug. 17, 2010, which is incorporated herein by reference in its entirety). The reasons for the detrimental cognitive and functional effects of semagacestat in AD patients are unclear. The drug-induced accumulation in the brain of the neurotoxic C-terminal fragment of APP (CTFβ or C99) resulting from the γ-secretase block (see Gitter B D, et al., Neurobiol, Aging, 25 (Suppl 2): 5571 (2004), which is incorporated herein by reference in its entirety) and the tendency of the drug to increase brain (see Lanz T A, et al., J. Pharmacol. Exp. Ther., 319: 924-933 (2006), which is incorporated herein by reference in its entirety) and CSF (see Bateman R J, et al. Ann. Neurol., 66: 48-54 (2009), which is incorporated herein by reference in its entirety) levels of the neurotoxic Aβ42 peptide could play a role (see Imbimbo B P, et al., Curr. Opin. Investig. Drugs, 10: 721-730 (2009), which is incorporated herein by reference in its entirety). Indeed, semagacestat has been shown to decrease dendritic spine density in mice (see Bittner T, et al., J. Neurosci., 2009; 29: 10405-10409 (2009), which is incorporated herein by reference in its entirety). Thus, in order to get safe and effective anti-AD drugs, Aβ42 may need to be selectively lowered without inducing abnormal accumulation of CTFβ and without affecting the proteolysis of Notch. This can be realized by modulating rather than inhibiting γ-secretase.
The first compounds of this type are certain non-steroidal anti-inflammatory drugs (NSAIDs) that are capable of altering the cleavage properties of γ-secretase to lower the production of Aβ42 and increase the formation of a shorter 38-residue species (Aβ38) (see Weggen S, et al., Nature, 414: 212-216 (2001), which is incorporated herein by reference in its entirety). These compounds include ibuprofen, sulindac sulfide, indomethacin, flurbiprofen, and others. The ability of these NSAIDs to modulate Aβ production is not related to their inhibitory activity on cyclooxygenase (COX). Binding of these NSAIDs to APP is more efficient than to Notch and thus their effects on Notch processing are minor (see Kukar T, et al., Curr. Top. Med. Chem., 8: 47-53 (2008), which is incorporated herein by reference in its entirety). These NSAIDs are not very potent toward lowering Aβ production and structural modifications of these molecules have been proposed (see Peretto I, et al., Curr. Top. Med. Chem., 8: 38-46 (2008), which is incorporated herein by reference in its entirety).
Certain new γ-secretase modulators endowed with selective Aβ42-lowering properties but devoid of COX inhibitory activity, thus suitable for chronic use in AD patients, have been reported (see Peretto I, et al., J. Med. Chem., 48: 5705-5720 (2005), which is incorporated herein by reference in its entirety). Within this new chemical series, 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5074) proved to be of major interest. In human neuroglioma cells over-expressing the Swedish mutated APP (H4swe), CHF 5074 preferentially lowers Aβ42 secretion with an IC50 of 3.6 μM (see Imbimbo B P, et al., J. Pharmacol. Exp. Ther., 323: 822-830 (2007), which is incorporated herein by reference in its entirety). CHF 5074 does not display inhibitory activity on COX-1 and COX-2 enzymes when employed at concentrations up to 100 μM and 300 μM, respectively (see Imbimbo B P, et al. Pharmacol. Res., 55: 318-328 (2007), which is incorporated herein by reference in its entirety). At 5 μM, no effects were observed on Notch intracellular cleavage in human embryonic kidney 293 swe cells (see Imbimbo B P, et al., J. Pharmacol. Exp. Ther., 323: 822-830 (2007), which is incorporated herein by reference in its entirety). At 100 μM, CHF 5074 does not alter the expression profile of several NICD-responsive genes (see Imbimbo B P, et al., Pharmacol. Res., 55: 318-328 (2007), which is incorporated herein by reference in its entirety). In mice and rats, CHF 5074 appears to be well absorbed orally (74% and 50%, respectively) and slowly eliminated from plasma (t1/2=12 and 20 hours, respectively) (see Peretto I, et al., J. Med. Chem., 48: 5705-5720 (2005), which is incorporated herein by reference in its entirety). CHF 5074 brain levels represent 3-14% of the corresponding plasma concentrations. In guinea-pigs, CHF 5074 shows a prolonged plasma elimination half-life (t1/2≈30 hours) after oral administration and a brain penetration of 3-9%. In dogs, the drug is quantitatively absorbed by oral route (80-100%) and is eliminated slowly from plasma (t1/2≈24 hours). Brain to plasma drug levels range between 5 and 7%. The main metabolite of CHF 5074 appears to be the glucuronide conjugated derivative.
Pharmacological studies in transgenic mouse models of AD have shown that CHF 5074 is active from neuropathological and behavioral points of view at oral doses of 60 mg/kg/day (see Imbimbo B P, et al., J. Pharmacol. Exp. Ther., 323: 822-830 (2007); Imbimbo B P, et al., Br. J. Pharmacol., 159: 982-993 (2008); and Imbimbo B P, et al., J. Alzheimers Dis., 20: 159-173 (2010), all of which are incorporated herein by reference in their entireties). At this dose level, the drug appears to be well tolerated by mice even after prolonged treatment for 4-9 months.
More in general, across several pathological conditions, an increasing number of patients are being identified who do not meet the diagnostic criteria for dementia but nonetheless have significant memory or cognitive impairment, defined as Mild Cognitive Impairment. Alzheimer's disease (AD) is the result of long-term pathophysiologic processes starting years before the onset of clinical symptoms. Therapeutic interventions should thus be started early on in the disease course so that patients can achieve the maximum benefit. Interest has therefore focused on identifying signs of cognitive decline as early as possible in the evolution of the disease. Several attempts have been made to characterize the cognitive impairment without dementia commonly seen in elderly individuals (see Ritchie K, et al., Lancet; 355: 225-228 (2000), which is incorporated herein by reference in its entirety). Mild cognitive impairment (MCI) is one of several concepts describing a cognitive state between normal aging and dementia: “MCI is a syndrome defined as cognitive decline greater than that expected for an individual's age and education level but that does not interfere notably with activities of daily living [ADL]” (see Gauthier S, et al., Lancet, 367: 1262-1270 (2006), which is incorporated herein by reference in its entirety). Subjects with MCI are at increased risk to develop dementia. Although “there is no agreement in the field on a single set of criteria for MCI” (see Petersen R C, et al., J. Intern. Med., 256: 183-194 (2004), which is incorporated herein by reference in its entirety), criteria for MCI proposed in 1999 by investigators at Mayo Clinic (see Petersen R C, et al., Arch. Neurol., 56: 303-308 (1999) and Petersen R C, et al., Arch. Neurol., 66: 1447-1455 (2009), both of which are incorporated herein by reference in their entireties) have been largely used in clinical studies since then:
1) Memory complaint, preferably corroborated by an informant;
2) Memory impairment documented according to appropriate reference values;
3) Essentially normal performance in non-memory cognitive domains;
4) Generally preserved activities of daily living;
5) Not demented.
In the case of non-amnestic MCI patients, criterium 2 of the original Petersen et al's criteria (see Petersen R C, et al., Arch. Neurol., 56: 303-308 (1999), which is incorporated herein by reference in its entirety) is also integrated with the diagnostic decision process suggested by Petersen (see Petersen R C, et al., J. Intern. Med., 256: 183-194 (2004), which is incorporated herein by reference in its entirety): “Once the clinician has determined that the person is neither normal nor demented” but memory is not impaired, the other cognitive functions will be assessed to determine if the impairment involves other nonmemory domains.
Thus, Mild Cognitive Impairment (MCI) is a condition characterized by mild recent memory loss without dementia or significant impairment of other cognitive functions to an extent that is beyond that expected for age or educational background. Criteria for diagnosis of MCI are: memory complaint; abnormal activities of daily living; abnormal general cognitive functioning; abnormal memory for age; not demented.
The number of patients falling in the categories of MCI, Age-Associated Memory Impairment, Age-Related Cognitive Decline or similar diagnostic categories is staggering. For example, according to the estimates of Barker et al., Br. J. Psychiatry, 167(5):642-8 (1995), which is incorporated herein by reference in its entirety, there are more than 16 million people with Age Associated Memory Impairment in the U.S. alone.
An advisory panel to the US Food and Drug Administration ruled on Mar. 13, 2001, that MCI, “a condition separate from dementia in Alzheimer's Disease (AD),” is a valid target for new drug therapies, regardless of whether a particular drug also slows the progression to dementia.
However, so far the drugs that are being used in the treatment of this disease only have mild, temporary effects. Therefore cognitive impairment is still an area of high unmet medical need with no effective drugs. The moderate and inconsistent effect observed with some drugs, e.g. cholinesterase inhibitors, indicates that more effective and safe treatments are needed.